With the increasing longevity of the human population, there is increased urgency to understand the consequences of aging on immunity to infections and to develop preventative or therapeutic strategies to counteract age-associated immune decline. Immune control of persistent viral infections is a problem associated with aging, as illustrated by the well-documented example of reactivation of the alpha-herpesvirus, varicella-zoster in the elderly, causing postherpetic neuralgia (Shingles). The human gamma-herpesviruses, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, are important human pathogens, associated with lymphoproliferative disorders and various maligancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and Kaposi's sarcoma. It is therefore critical that we understand the ability of aged individuals to control these infections. In the current proposal, we will exploit a well-characterized mouse model, HV68, to study the impact of aging on immune control of this important class of persistent viruses. Accumulating data suggest that CD4 T cells, CDS T cells and antibodies all contribute to immune control of viral latency in young mice. Our preliminary data show that virus-specific antibody liters are maintained for over two years after infection, but that there is a progressive decline in neutralizing activity with age. Proposed experiments to understand the functional implications and mechanisms underlying this striking and novel observation are outlined in three specific Aims in this supplemental application. In Aim 1, we will determine the functional impact of declining neutralizing antibodies for immune control of a persistent y-herpesvirus infection in aged mice. In Aim 2, we will identify differences in the antibody and virus-specific B cells and plasma cells associated with declining neutralizing activity in aged mice. In Aim 3, we will identify mechanisms underlying the decline in neutralizing antibodies. We will determine the impact of the age-associated decline in CD4 function and determine whether declining neutralizing titers are unique to persistent viruses. These studies have implications not only for immune control of persistent infections in aged individuals, but may also have general implications for understanding mechanisms for long-term maintenance of humoral immunity. [unreadable] [unreadable] As people age, their immune function declines. This is significant in terms of their ability to handle new infections and to be effectively vaccinated, but also for their ability to maintain immune control of persistent infections. The reactivation of the chicken pox virus in the elderly to cause Shingles is a classic example. In this project we will study the impact of age on immune control of another group of persistent viruses, the gamma-herpesviruses, which are associated with the development of several types of cancer. We will use a mouse model, in which we can carry out well-controlled studies not possible in humans. [unreadable] [unreadable] [unreadable]